This Funding Opportunity Announcement (FOA) seeks to
support basic and translational research on the neurobiology of sex
differences. Specifically, NIMH and ORWH solicit Exploratory/Developmental (R21)
grant applications that explicitly test hypotheses regarding neural
mechanisms underlying sex differences relevant to mental health. Applications
should articulate a strong rationale for how the proposed project will
significantly advance our understanding of the etiology and/or underlying
pathophysiology of mental disorders in males and females.

Key Dates

Posted Date

December 13, 2011

Open Date (Earliest Submission Date)

February 13, 2012

Letter of Intent Due Date

February 13, 2012

Application Due Date(s)

March 13, 2012, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Not Applicable.

Scientific Merit Review

July 2012

Advisory Council Review

October 2012

Earliest Start Date(s)

January 2013

Expiration Date

March 14, 2012

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in
the SF
424 (R&R) Application Guide, except where instructed to do otherwise
(in this FOA or in a Notice from the NIH Guide for Grants and
Contracts). Conformance to all requirements (both in the
Application Guide and the FOA) is required and strictly enforced. Applicants
must read and follow all application instructions in the Application Guide as
well as any program-specific instructions noted in Section IV. When the program-specific
instructions deviate from those in the Application Guide, follow the program-specific
instructions. Applications that do not comply with these instructions may
be delayed or not accepted for review.

This Funding Opportunity Announcement (FOA) issued by the
National Institute of Mental Health (NIMH) and the Office of Research on
Women's Health (ORWH), National Institutes of Health, seeks to support basic
and translational research on the neurobiology of sex differences.
Specifically, NIMH and ORWH solicit Exploratory/Developmental (R21) grant applications
that explicitly test hypotheses regarding neural mechanisms underlying sex
differences relevant to mental health. Applications should articulate a strong
rationale for how the proposed project will significantly advance our
understanding of the etiology and/or underlying pathophysiology of mental
disorders in males and females.

Research supported by this initiative will aim to understand
how interactions between sex chromosomes, steroid hormones and environment
shape sexually dimorphic neural pathways and behavior. Research projects
funded under this FOA will aim to advance our understanding of how sexual
dimorphisms influence clinical symptoms and age of onset of mental disorders. Periods
of developmental divergence between the sexes, periods of rapid developmental
change, and periods during which environmental influences are particularly
strong present an opportunity for understanding sex-specific neurodevelopmental
trajectories. As a result, studies testing developmental questions are
strongly encouraged under this funding opportunity. Genetic variants with
known associations to mental illness offer an opportunity to explore how
genetic risk is linked to changes in brain function and circuitry. Sex
differences in the prevalence and symptom profiles of mental disorders suggest
sex differences in genetic risk. Therefore, studies investigating sex
differences in genotype association or gene expression are encouraged under
this funding opportunity.

Background

The NIMH has defined four overarching objectives in a Strategic
Plan designed to carry out our mission of transforming the understanding
and treatment of mental illnesses through basic and clinical research.
Two Strategic Objectives are directly addressed by this FOA. The first,
to promote discovery in the brain and behavioral sciences to fuel research on
the causes of mental disorders, is met through basic, translational and
clinical research that investigates genetic, neurobiological, behavioral,
environmental and experiential factors in the etiology of disorders. The
second objective focuses on understanding where, when and how to intervene by
charting the trajectories of mental disorders over the lifespan in an effort to
identify appropriate points of intervention to hasten recovery or prevent onset
of illness.

An individual’s sex can influence susceptibility,
prevalence, and age of onset for psychiatric disorders. Disorders that emerge
early in development, such as autism, ADHD, Tourette Syndrome, and early-onset
schizophrenia, tend to be more prevalent in males. Disorders with onset in
adolescence or adulthood, such as major depression, anxiety disorders, and
eating disorders, are more prevalent in females. Despite these clear
epidemiological trends, very little is known about the precise timing, neural
circuitry, or mechanisms underlying the expression of sex differences in mental
disorders.

Sex differences have been largely overlooked in many
research studies because of prevailing practices and biases in the field (Cahill,
2010; Nature, 2010; Office of Research on Women’s Health, 2010). Sex is often
not considered in analyses, frequently due to a lack of power to address this
question. Animal research studies frequently include only one sex in their
experimental designs. Also lacking are theoretical models of disease that
attempt to explain how neurobiological sex differences interact with other
biological or environmental factors to confer risk and resilience for mental
disorders. Moreover, because sex differences may be one factor underlying
individual differences in response to treatments and interventions, research on
sex differences related to the etiology of mental disorders may provide
information fundamental to the development of personalized interventions.

Objectives

Sex differences are often driven by organizational effects
during early brain development or activational effects related to variation in
circulating hormone levels. A significant area of research concerns the
precise timing of sex-specific genetic, epigenetic, and hormonal events during
neurodevelopment. This FOA encourages applications that focus on interactions
between such events and the resulting long-lasting sexual dimorphisms in
cognitive, affective or social function. Research using animal and/or human
subjects is encouraged.

One major objective of this initiative is to encourage
researchers who have not previously focused on sex differences to include sex
as a factor in their designs and analyses. Another major goal is to stimulate
the development of conceptual frameworks that hypothesize how sex influences
risk for mental illness. It is expected that findings from these
investigations will enhance our ability to predict, diagnose, and intervene in
mental disorders. Because the intent of this FOA is to foster new approaches
emphasizing neuronal mechanisms rather than existing lines of investigation,
the FOA emphasizes exploratory, high-risk, and potentially groundbreaking
studies.

Examples of research topics include, but are not limited to,
the following:

Studies using human post-mortem tissue to examine sex differences
in gene transcription and expression in normative and pathological development.

Studies of neural mechanisms of sex differences in the age of
onset and clinical symptoms of mental disorders.

Brain mechanisms contributing to sex differences in treatment
effectiveness for mental disorders to inform future development of novel,
personalized treatments.

Secondary analyses of existing longitudinal imaging data-sets to
address sex differences in brain development and connectivity patterns,
especially in individuals at risk for mental disorders.

The description of the research project should include concrete
indicators of progress and how these indicators will be used to inform the next
phase of research on sex differences in mental health. Appropriate indicators
may include, but are not limited to, recruitment schedules, interim data
analyses, and/or a timeline for administrative and scientific accomplishments.
Progress indicators should be included in each annual progress report and as
part of the final report for the grant.

Although a formal data sharing plan is not required for
applications submitted in response to this FOA, applicants are strongly
encouraged to consider and should address data sharing in the application. Data
collection, data description, and management procedures should be designed and
piloted with future data sharing in mind (e.g., development of a data
dictionary, data quality assurance procedures, and/or inclusion of relevant
language in consent forms to allow future data sharing where appropriate).

Responsive applications must include both males and females.
Specific aims must explicitly test hypotheses regarding sex differences. Hypotheses
must address neural mechanisms and not focus solely on behavioral or
epidemiological outcomes. Relevant applications must consider behaviors
related to mental disorders and/or address how sexually dimorphic neural
processes confer risk or impact resilience for mental disorders. Responsive
applications are also required to articulate a strong rationale for how the
proposed project will significantly advance our understanding of the etiology
and/or underlying pathophysiology of mental disorders. The NIMH will decline
applications that are not considered central to the NIMH mission and research
priorities. Applications that focus on reproductive behaviors, aggression
outside of the context of serious mental illness, or primary sensorimotor
processing will not be considered responsive to this announcement. Applicants
are strongly encouraged to consult the appropriate program official, listed in Section
VII, to discuss the relevance of their proposed work to the NIMH mission as
well as to ensure that proposed studies do not duplicate projects currently
supported.

Applicant organizations must complete the following registrations
as described in the SF 424 (R&R) Application Guide to be eligible to apply
for or receive an award. Applicants must have a valid Dun and Bradstreet
Universal Numbering System (DUNS) number in order to begin each of the following
registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s))
must also work with their institutional officials to register with the eRA
Commons or ensure their existing eRA Commons account is affiliated with the eRA
Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant
organizations are strongly encouraged to start the registration process at
least 4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal Investigator(s))

Any individual(s) with the skills, knowledge, and resources
necessary to carry out the proposed research as the Program Director(s)/Principal
Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH support.

Applicant organizations may submit more than one application,
provided that each application is scientifically distinct.

NIH will not accept any application in response to this FOA
that is essentially the same as one currently pending initial peer review
unless the applicant withdraws the pending application. NIH will not accept any
application that is essentially the same as one already reviewed.

Section IV. Application and Submission Information

1. Requesting an
Application Package

Applicants must download the SF424 (R&R) application
package associated with this funding opportunity using the “Apply for Grant
Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in
the SF424
(R&R) Application Guide, except where instructed in this funding
opportunity announcement to do otherwise. Conformance to the requirements in
the Application Guide is required and strictly enforced. Applications that are
out of compliance with these instructions may be delayed or not accepted for
review.

Although a letter of intent is not required, is not binding,
and does not enter into the review of a subsequent application, the information
that it contains allows IC staff to estimate the potential review workload and
plan the review.

By the date listed in Part 1. Overview
Information, prospective applicants are asked to submit a letter of intent
that includes the following information:

The forms package associated with this FOA includes all
applicable components, mandatory and optional. Please note that some
components marked optional in the application package are required for
submission of applications for this FOA. Follow all instructions in the SF424
(R&R) Application Guide to ensure you complete all appropriate “optional”
components.

Page Limitations

All page limitations described in the SF424 Application
Guide and the Table of
Page Limits must be followed.

PHS 398 Research Plan Component

All instructions in the SF424 (R&R) Application Guide
must be followed, with the following additional instructions:

Progress Indicators

The Research Strategy section should describe
concrete indicators of progress toward the research project objectives. These
can include specific and feasible measures of progress, potential data sources,
and a timeline for major milestones. The measures included should assess the
scientific accomplishments, both yearly and overall, of the research project. This
should be included within the page limit of the Research Strategy. Progress indicators
should be included in each annual progress report and as part of the final
report of the grant.

Resource Sharing Plan

Individuals are required to comply with the
instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model
Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424
(R&R) Application Guide.

Appendix

Do not use the Appendix to circumvent page limits. Follow
all instructions for the Appendix as described in the SF424 (R&R)
Application Guide.

Foreign Institutions

Foreign (non-US) institutions must follow policies described
in the NIH
Grants Policy Statement, and procedures for foreign institutions described
throughout the SF424 (R&R) Application Guide.

3. Submission Dates and
Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in
advance of the deadline to ensure they have time to make any application
corrections that might be necessary for successful submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants
across all Federal agencies. Applicants must then complete the submission
process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants
administration.

Applicants
are responsible for viewing their application in the eRA Commons to ensure accurate
and successful submission.

Information on the submission process and a definition of
on-time submission are provided in the SF424 (R&R) Application Guide.

For assistance with your electronic application or for more information on the electronic submission
process, visit Applying
Electronically.

Important
reminders:All PD(s)/PI(s) must include their eRA Commons ID in the
Credential fieldof the Senior/Key Person Profile Component of the SF
424(R&R) Application Package. Failure to register in the Commons and
to include a valid PD(s)/PI(s) Commons ID in the credential field will prevent
the successful submission of an electronic application to NIH.

The applicant organization must ensure that the DUNS number it provides on the
application is the same number used in the organization’s profile in the eRA
Commons and for the Central Contractor Registration (CCR). Additional
information may be found in the SF424 (R&R) Application Guide.

Upon receipt, applications will be evaluated for
completeness by the Center for Scientific Review and responsiveness by NIMH,
NIH. Applications that are incomplete and/or nonresponsive will not be
reviewed.

In order to expedite review, applicants are requested to notify
the NIMH Referral Office by email at nimhreferral@mail.nih.gov when the application has been submitted. Please include the FOA number and
title, PD(S)/PI(s) name, and title of the application.

Post Submission Materials

Applicants are required to follow the instructions for
post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review Information

1.
Criteria

Only the review criteria described below will be considered
in the review process. As part of the NIH mission,
all applications submitted to the NIH in support of biomedical and behavioral
research are evaluated for scientific and technical merit through the NIH peer
review system.

For this particular announcement, note the following:

The R21 exploratory/developmental grant supports
investigation of novel scientific ideas or new model systems, tools, or
technologies that have the potential for significant impact on biomedical or
biobehavioral research. An R21 grant application need not have extensive
background material or preliminary information. Accordingly, reviewers will focus
their evaluation on the conceptual framework, the level of innovation, and the
potential to significantly advance our knowledge or understanding. Appropriate
justification for the proposed work can be provided through literature
citations, data from other sources, or, when available, from
investigator-generated data. Preliminary data are not required for R21
applications; however, they may be included if available.

Overall Impact

Reviewers will provide an overall impact/priority score to
reflect their assessment of the likelihood for the project to exert a
sustained, powerful influence on the research field(s) involved, in
consideration of the following review criteria and additional review criteria
(as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in
the determination of scientific merit, and give a separate score for each. An
application does not need to be strong in all categories to be judged likely to
have major scientific impact. For example, a project that by its nature is not
innovative may be essential to advance a field.

Significance

Does the project address an
important problem or a critical barrier to progress in the field? If the aims
of the project are achieved, how will scientific knowledge, technical
capability, and/or clinical practice be improved? How will successful
completion of the aims change the concepts, methods, technologies, treatments,
services, or preventative interventions that drive this field? Does the study focus on neurobiological systems relevant to human mental disorders? Does
the research project further the understanding of the neural mechanisms by
which sex differences confer risk for or influence on resilience to mental
illnesses? Will the research project lead to greater understanding of how
interactions between sex chromosomes, steroid hormones, and environment shape
sexually dimorphic neural pathways and behavior? Will the research project
lead to identification/clarification of sexually-dimorphic points of
vulnerability and developmental divergence? Does the research project address
how sex differences in neurodevelopment confer vulnerability or protection in
individuals at familial/genetic risk for mental disorders? Will this research
facilitate improved understanding of how sexual dimorphisms influence the age
of onset and clinical symptoms of mental disorders? Will the research project
lay the foundation for future research to improve personalized prevention and
interventions?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other
researchers well suited to the project? If Early Stage Investigators or New
Investigators, or in the early stages of independent careers, do they have
appropriate experience and training? If established, have they demonstrated an
ongoing record of accomplishments that have advanced their field(s)? If the
project is collaborative or multi-PD(s)/PI(s), do the investigators have
complementary and integrated expertise; are their leadership approach,
governance and organizational structure appropriate for the project?

Innovation

Does the application challenge and
seek to shift current research or clinical practice paradigms by utilizing
novel theoretical concepts, approaches or methodologies, instrumentation, or
interventions? Are the concepts, approaches or methodologies, instrumentation,
or interventions novel to one field of research or novel in a broad sense? Is a
refinement, improvement, or new application of theoretical concepts, approaches
or methodologies, instrumentation, or interventions proposed? Does the application develop or test novel technologies that
will facilitate the measurement or analysis of sex specific neural mechanisms
such as techniques for visualization and manipulation of in vivo cellular
function; novel methods for in vivo examination of epigenetic influences,
especially in human brain tissue; new molecular and genetic approaches to study
the effect of developmental stage, experience, and hormones?

Approach

Are the overall strategy, methodology, and analyses
well-reasoned and appropriate to accomplish the specific aims of the project?
Are potential problems, alternative strategies, and benchmarks for success
presented? If the project is in the early stages of development, will the
strategy establish feasibility and will particularly risky aspects be
managed?

If the project involves clinical research, are the plans for 1) protection of
human subjects from research risks, and 2) inclusion of minorities and members
of both sexes/genders, as well as the inclusion of children, justified in terms
of the scientific goals and research strategy proposed?

Does the study have sufficient power to test
hypotheses regarding sex differences? Does the study include both male and
female subjects (humans or animals)? Is
the evaluation plan well-defined, including (1) specific and feasible measures
of progress, (2) adequate and available data sources, and (3) a timeline for
major milestones?

Environment

Will the scientific environment in which the work
will be done contribute to the probability of success? Are the institutional
support, equipment and other physical resources available to the investigators
adequate for the project proposed? Will the project benefit from unique
features of the scientific environment, subject populations, or collaborative
arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will
evaluate the following additional items while determining scientific and
technical merit, and in providing an overall impact/priority score, but will
not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does
not involve one of the six categories of research that are exempt under 45 CFR
Part 46, the committee will evaluate the justification for involvement of human
subjects and the proposed protections from research risk relating to their
participation according to the following five review criteria: 1) risk to
subjects, 2) adequacy of protection against risks, 3) potential benefits to the
subjects and others, 4) importance of the knowledge to be gained, and 5) data
and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more
of the six categories of research that are exempt under 45 CFR Part 46, the
committee will evaluate: 1) the justification for the exemption, 2) human
subjects involvement and characteristics, and 3) sources of materials. For
additional information on review of the Human Subjects section, please refer to
the Human
Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and
Children

When the proposed project involves clinical research,
the committee will evaluate the proposed plans for inclusion of minorities and
members of both genders, as well as the inclusion of children. For additional
information on review of the Inclusion section, please refer to the Human
Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live
vertebrate animals as part of the scientific assessment according to the
following five points: 1) proposed use of the animals, and species, strains,
ages, sex, and numbers to be used; 2) justifications for the use of animals and
for the appropriateness of the species and numbers proposed; 3) adequacy of
veterinary care; 4) procedures for limiting discomfort, distress, pain and
injury to that which is unavoidable in the conduct of scientifically sound
research including the use of analgesic, anesthetic, and tranquilizing drugs
and/or comfortable restraining devices; and 5) methods of euthanasia and reason
for selection if not consistent with the AVMA Guidelines on Euthanasia. For
additional information on review of the Vertebrate Animals section, please
refer to the Worksheet
for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures
proposed are potentially hazardous to research personnel and/or the
environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

Additional Review Considerations

As applicable for the project proposed, reviewers will
consider each of the following items, but will not give scores for these items,
and should not consider them in providing an overall impact/priority score.

Applications from Foreign
Organizations

Reviewers will assess whether the project presents
special opportunities for furthering research programs through the use of
unusual talent, resources, populations, or environmental conditions that exist
in other countries and either are not readily available in the United States or
augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in
this section of the application, including 1) the Select Agent(s) to be used in
the proposed research, 2) the registration status of all entities where Select
Agent(s) will be used, 3) the procedures that will be used to monitor
possession use and transfer of Select Agent(s), and 4) plans for appropriate
biosafety, biocontainment, and security of the Select Agent(s).

Reviewers will consider whether the budget and the
requested period of support are fully justified and reasonable in relation to
the proposed research.

2. Review and Selection
Process

Applications will be evaluated for scientific and technical
merit by (an) appropriate Scientific Review Group(s) convened by the NIMH, in accordance with NIH peer
review policy and procedures, using the stated review
criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

May undergo a selection process in which only those applications
deemed to have the highest scientific and technical merit (generally the top
half of applications under review) will be discussed and assigned an overall impact/priority
score.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds
with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review
by the National Advisory Mental Health Council. The following will be
considered in making funding decisions:

Scientific and technical merit of the proposed project as
determined by scientific peer review.

Availability of funds.

Relevance of the proposed project to program priorities.

3. Anticipated Announcement
and Award Dates

After the peer review of the application is completed, the
PD(s)/PI(s) will be able to access his or her Summary Statement (written
critique) via the eRA Commons.

If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided
to the applicant organization for successful applications. The NoA signed by
the grants management officer is the authorizing document and will be sent via
email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection
of an application for award is not an authorization to begin performance. Any
costs incurred before receipt of the NoA are at the recipient's risk. These
costs may be reimbursed only to the extent considered allowable pre-award costs.

A final progress report, invention
statement, and the expenditure data portion of the Federal Financial Report are
required for closeout of an award, as described in the NIH Grants
Policy Statement.

The Federal Funding Accountability and Transparency Act of
2006 (Transparency Act), includes a requirement for awardees of Federal grants
to report information about first-tier subawards and executive compensation
under Federal assistance awards issued in FY2011 or later. All awardees of
applicable NIH grants and cooperative agreements are required to report to
the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants
Policy Statement for additional information on this reporting
requirement.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity
and welcome the opportunity to answer questions from potential applicants.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and
under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.